Laboratory Testing for Hemochromatosis
Order fasting transferrin saturation (TS) and serum ferritin simultaneously as the initial screening tests for hemochromatosis. 1, 2
Initial Screening Tests
The diagnostic workup begins with two essential iron studies that should be obtained together rather than relying on a single test:
- Transferrin saturation (TS): Should be drawn in the morning (fasting does not improve diagnostic utility per the most recent guidelines) 1
- Serum ferritin: Obtained simultaneously with TS 2
Interpretation Thresholds for Iron Overload
Females:
- TS >45% AND ferritin >200 µg/L suggests iron overload 1
Males:
- TS >50% AND ferritin >300 µg/L suggests iron overload 1
If either test is abnormal (TS ≥45% or ferritin above the upper limit of normal), proceed to genetic testing 2.
Confirmatory Genetic Testing
HFE genotyping for p.C282Y mutation should be performed in individuals of European origin with biochemical evidence of iron overload (as defined above) with or without clinical symptoms 1. This is the critical next step after abnormal iron studies.
The HFE test should specifically evaluate:
- p.C282Y homozygosity (most common, >80% of cases)
- p.C282Y/H63D compound heterozygosity
- p.C282Y heterozygosity 2
Additional Laboratory Tests for Risk Stratification
Once hemochromatosis is confirmed, obtain these tests to assess for cirrhosis risk:
- Liver enzymes (ALT/AST): Elevated levels combined with ferritin >1000 µg/L predict cirrhosis risk 2
- Platelet count: Count <200 combined with ferritin >1000 µg/L and elevated aminotransferases predicts cirrhosis in 80% of C282Y homozygotes 2
Key prognostic marker: Ferritin <1000 µg/L is an accurate predictor for the absence of cirrhosis 2.
Important Caveats
Ferritin Limitations
Ferritin is not specific for iron overload—it is also an acute phase reactant elevated in:
- Fatty liver disease and metabolic syndrome
- Alcohol-related liver disease
- Inflammation and infection
- Malignancy
- Hepatocellular necrosis 1
Critical point: An elevated ferritin with normal TS may be nonspecific and not indicate hemochromatosis. Conversely, iron overload can exist with elevated ferritin but normal TS, particularly in non-HFE hemochromatosis or C282Y/H63D compound heterozygotes 2.
Transferrin Saturation Limitations
Elevated TS can occur in conditions with decreased transferrin levels:
- Alcohol-related liver disease or cirrhosis
- Dyserythropoiesis
- Chronic hemolysis
- Transfusion-dependent states 1
Family Screening Protocol
For first-degree relatives of confirmed hemochromatosis patients, order both tests simultaneously at a single visit:
- HFE genotyping
- Transferrin saturation and ferritin 2
This dual approach allows for immediate risk assessment without requiring multiple visits.
When to Consider Advanced Testing
If HFE testing is negative but iron overload persists without alternative explanation, consider: